EP0046661B1 - Rapamycin derivatives - Google Patents

Rapamycin derivatives Download PDF

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Publication number
EP0046661B1
EP0046661B1 EP81303794A EP81303794A EP0046661B1 EP 0046661 B1 EP0046661 B1 EP 0046661B1 EP 81303794 A EP81303794 A EP 81303794A EP 81303794 A EP81303794 A EP 81303794A EP 0046661 B1 EP0046661 B1 EP 0046661B1
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EP
European Patent Office
Prior art keywords
rapamycin
monoacetyl
derivatives
derivative
diacetyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP81303794A
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German (de)
French (fr)
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EP0046661A1 (en
Inventor
Sumanas Rakhit
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Canada Inc
Original Assignee
Ayerst Mckenna and Harrison Inc
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Application filed by Ayerst Mckenna and Harrison Inc filed Critical Ayerst Mckenna and Harrison Inc
Priority to AT81303794T priority Critical patent/ATE7920T1/en
Publication of EP0046661A1 publication Critical patent/EP0046661A1/en
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Publication of EP0046661B1 publication Critical patent/EP0046661B1/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • This invention relates to novel monoacetyl and diacetyl derivatives of rapamycin, to processes for their preparation, to methods of using the derivatives and to pharmaceutical compositions of the derivatives.
  • the derivatives are useful as antifungal antibiotics.
  • Rapamycin is an antifungal antibiotic described by C. Vezina et al., J. Antibiot., 28, 721 (1975), S. N. Sehgal et al., J. Antibiot., 28, 727 (1975), S. N. Sehgal et al., U.S. Patent 3,929,992, issued December 30th, 1975 and S. N. Sehgal et al., U.S. Patent 3,993,749, issued November 23, 1976. The latter two patents are herein incorporated by reference. The structure of rapamycin is described by D. C. Neil, et al., Can. J. Chem., 56, 2491 (1978).
  • Rapamycin is extracted from a streptomycete (Streptomyces hygroscopicus NRRL 5491) isolated from an Easter Island soil sample and is particularly effective against Candida albicans both in vitro and in vivo, H. A. Baker et al., J. Antibiot., 31, 539 (1978). Streptomyces hygroscopicus NRRL 5491 samples were deposited 23rd June 1972 without restrictions with the Northern Utilization and Research Division, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Illinois, U.S.A. A report by R. R. Martel et al., Can. J.
  • rapamycin for the prevention of the development of experimental immunopathies. Recently, rapamycin was shown to be an effective agent for treating carcinogenic tumors in a mammal by S. N. Sehgal and C. Vezina, United States Patent Application Serial No. 957,626, filed November 3, 1978. In Belgium, a corresponding application of the latter application issued as Belgium Patent No. 877,700 on January 14, 1980.
  • This invention provides monoacetyl or diacetyl derivatives of rapamycin.
  • An antifungal composition comprising a monoacetyl or diacetyl derivative of rapamycin and a carrier.
  • the carrier is a pharmaceutically acceptable carrier.
  • the monoacetyl and diacetyl derivatives of rapamycin inhibit the growth of pathogenic fungi in a mammal by administering to the mammal an effective antifungal amount of the monoacetyl or diacetyl derivative of rapamycin.
  • organic proton acceptor means the organic bases or amines, for instance, triethylamine, pyridine, N-ethylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene and the like.
  • the monoacetyl and diacetyl derivatives of rapamycin are useful as antifungal agents against pathogenic fungi; for example, Candida albicans.
  • the inhibitory activity of the derivatives are especially pronounced against Candida albicans.
  • the monoacetyl derivative exhibits a MIC of 0.04 mcg/ml and the diacetyl derivative exhibits a MIC of 2.5 mcg/ml.
  • the antifungal activity of the derivatives are demonstrated in standard tests used for this purpose, for example, in the tests described in "Antiseptics, Disinfectants, Fungicides and Sterilization", G. F. Reddish, Ed., 2nd ed., Lea and Febiger, Philadelphia, 1957 or by D. C. Grove and W. A. Randall in "Assay Methods of Antibiotics", Med. Encyl. Inc., New York 1955.
  • rapamycin derivative of this invention When employed as an antifungal agent in a mammal, it can be used alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice.
  • an antifungally effective amount of the derivative can be administered orally in solid form containing such excipients as starch, sugar, certain types of clay and so forth.
  • such an amount can be administered orally in the form of solutions or suspensions or the derivative can be injected parenterally.
  • the derivative can be used in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • solutes or suspending agents for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • the dosage of the present derivative will vary with the form of administration and the particular derivative chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less then the optimum dose of the derivative. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the derivative of this invention is most desirably administered at a concentration level that will generally afford antifungally effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 1.0 mg to about 250 mg per kilo per day, although as aforementioned variations will occur.
  • a dosage level that is in the range of from about 10 mg to about 100 mg per kilo per day is most desirably employed in order to achieve effective results.
  • the derivative can be employed topically.
  • topical application it may be formulated in the form of solutions, creams or lotions in pharmaceutically acceptable vehicles containing 0.1-5 per cent, preferably 2 per cent of the agent, and may be administered topically to the infected area of the skin.
  • the derivative also can be used for cleaning and disinfecting laboratory equipment, surgical instruments, locker rooms, or shower rooms of sensitive fungus organisms.
  • an alkanol having 1 to 6 carbon atoms preferably methanol
  • a non-ionic surface-active agent for example, polysorbate 80 U.S.P.
  • the monoacetyl and diacetyl derivatives of rapamycin can be useful as anticancer or antitumour agents.
  • the derivatives can be used to treat carcinogenic tumors in a mammal by administering to the mammal an antitumour effective amount of the derivative. More specifically, the derivatives can reduce tumor size in and prolong survival time of a tumor bearing mammal. The effectiveness of the derivatives in this respect can be demonstrated in the laboratory with rodents having transplanted tumors. Details of methods used to evaluate this effect are described in various publications; for example, R. I. Geran et al., Cancer Chemother. Rep., Part 3, 3, (No. 2) 1-103 (1972) and references therein. In addition, the protocols for the antitumour tests are available from the National Cancer Institute, Bethesda, Maryland, U.S.A. The mode of administration and compositions of the derivatives are similar to those described above for antifungal use.
  • the acetyl derivatives of rapamycin are prepared by the acetylation of rapamycin. Accordingly this invention provides a process for preparing a mono- or di-acetyl derivative of rapamycin which comprises acetylating rapamycin with an acetylating agent containing an acetyl group.
  • Acetylation of rapamycin may be carried out with an agent selected from acetyl iodide, bromide or chloride in the presence of an organic proton acceptor, preferably triethylamine or pyridine, for example at 0 to 50°C or 0.5 to 10 hours, to give the corresponding monoacetyl or diacetyl derivative of rapamycin.
  • a preferred method of acetylation is the reaction of rapamycin with acetic anhydride in an excess of the organic proton acceptor at 0 to 10°C for about one to three hours to obtain a separable mixture of the monoacetyl and diacetyl derivatives of rapamycin.

Abstract

Disclosed are monoacyl and diacyl derivatives of rapamycin, processes for their preparation, methods of using the derivatives and pharmaceutical compositions of the derivatives. The derivatives are useful, inter alia, as antifungal antibiotics.

Description

  • This invention relates to novel monoacetyl and diacetyl derivatives of rapamycin, to processes for their preparation, to methods of using the derivatives and to pharmaceutical compositions of the derivatives. The derivatives are useful as antifungal antibiotics.
  • Rapamycin is an antifungal antibiotic described by C. Vezina et al., J. Antibiot., 28, 721 (1975), S. N. Sehgal et al., J. Antibiot., 28, 727 (1975), S. N. Sehgal et al., U.S. Patent 3,929,992, issued December 30th, 1975 and S. N. Sehgal et al., U.S. Patent 3,993,749, issued November 23, 1976. The latter two patents are herein incorporated by reference. The structure of rapamycin is described by D. C. Neil, et al., Can. J. Chem., 56, 2491 (1978). Rapamycin is extracted from a streptomycete (Streptomyces hygroscopicus NRRL 5491) isolated from an Easter Island soil sample and is particularly effective against Candida albicans both in vitro and in vivo, H. A. Baker et al., J. Antibiot., 31, 539 (1978). Streptomyces hygroscopicus NRRL 5491 samples were deposited 23rd June 1972 without restrictions with the Northern Utilization and Research Division, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Illinois, U.S.A. A report by R. R. Martel et al., Can. J. Physiol., 55, 48 (1977) describes the use of rapamycin for the prevention of the development of experimental immunopathies. Recently, rapamycin was shown to be an effective agent for treating carcinogenic tumors in a mammal by S. N. Sehgal and C. Vezina, United States Patent Application Serial No. 957,626, filed November 3, 1978. In Belgium, a corresponding application of the latter application issued as Belgium Patent No. 877,700 on January 14, 1980.
  • This invention provides monoacetyl or diacetyl derivatives of rapamycin.
  • An antifungal composition is also provided comprising a monoacetyl or diacetyl derivative of rapamycin and a carrier. For pharmaceutical applications the carrier is a pharmaceutically acceptable carrier.
  • The monoacetyl and diacetyl derivatives of rapamycin inhibit the growth of pathogenic fungi in a mammal by administering to the mammal an effective antifungal amount of the monoacetyl or diacetyl derivative of rapamycin.
  • The term "organic proton acceptor" as used herein means the organic bases or amines, for instance, triethylamine, pyridine, N-ethylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene and the like.
  • The monoacetyl and diacetyl derivatives of rapamycin are useful as antifungal agents against pathogenic fungi; for example, Candida albicans. The inhibitory activity of the derivatives are especially pronounced against Candida albicans. Against this fungi, the monoacetyl derivative exhibits a MIC of 0.04 mcg/ml and the diacetyl derivative exhibits a MIC of 2.5 mcg/ml.
  • The antifungal activity of the derivatives are demonstrated in standard tests used for this purpose, for example, in the tests described in "Antiseptics, Disinfectants, Fungicides and Sterilization", G. F. Reddish, Ed., 2nd ed., Lea and Febiger, Philadelphia, 1957 or by D. C. Grove and W. A. Randall in "Assay Methods of Antibiotics", Med. Encyl. Inc., New York 1955.
  • When the rapamycin derivative of this invention is employed as an antifungal agent in a mammal, it can be used alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, an antifungally effective amount of the derivative can be administered orally in solid form containing such excipients as starch, sugar, certain types of clay and so forth. Similarly, such an amount can be administered orally in the form of solutions or suspensions or the derivative can be injected parenterally. For parenteral administration the derivative can be used in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • The dosage of the present derivative will vary with the form of administration and the particular derivative chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less then the optimum dose of the derivative. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general the derivative of this invention is most desirably administered at a concentration level that will generally afford antifungally effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 1.0 mg to about 250 mg per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 10 mg to about 100 mg per kilo per day is most desirably employed in order to achieve effective results.
  • In addition, the derivative can be employed topically. For topical application it may be formulated in the form of solutions, creams or lotions in pharmaceutically acceptable vehicles containing 0.1-5 per cent, preferably 2 per cent of the agent, and may be administered topically to the infected area of the skin.
  • The derivative also can be used for cleaning and disinfecting laboratory equipment, surgical instruments, locker rooms, or shower rooms of sensitive fungus organisms. For such purposes it is preferred to use 0.1-10% solutions of the derivative in an alkanol having 1 to 6 carbon atoms, preferably methanol, diluted with 10-100 volumes of water containing 0.001-0.1 % of a non-ionic surface-active agent, for example, polysorbate 80 U.S.P., immediately before applying it to the objects to be cleaned and disinfected.
  • In addition to use as an antifungal agent, the monoacetyl and diacetyl derivatives of rapamycin can be useful as anticancer or antitumour agents. The derivatives can be used to treat carcinogenic tumors in a mammal by administering to the mammal an antitumour effective amount of the derivative. More specifically, the derivatives can reduce tumor size in and prolong survival time of a tumor bearing mammal. The effectiveness of the derivatives in this respect can be demonstrated in the laboratory with rodents having transplanted tumors. Details of methods used to evaluate this effect are described in various publications; for example, R. I. Geran et al., Cancer Chemother. Rep., Part 3, 3, (No. 2) 1-103 (1972) and references therein. In addition, the protocols for the antitumour tests are available from the National Cancer Institute, Bethesda, Maryland, U.S.A. The mode of administration and compositions of the derivatives are similar to those described above for antifungal use.
  • The acetyl derivatives of rapamycin are prepared by the acetylation of rapamycin. Accordingly this invention provides a process for preparing a mono- or di-acetyl derivative of rapamycin which comprises acetylating rapamycin with an acetylating agent containing an acetyl group. Acetylation of rapamycin may be carried out with an agent selected from acetyl iodide, bromide or chloride in the presence of an organic proton acceptor, preferably triethylamine or pyridine, for example at 0 to 50°C or 0.5 to 10 hours, to give the corresponding monoacetyl or diacetyl derivative of rapamycin. Replacement of the above described acetylating agent with acetic anhydride also gives the corresponding monoacetyl or diacetyl derivative of rapamycin. The above acetylations can be conducted in an inert organic solvent such as benzene, chloroform or dichloromethane or an excess of the organic proton acceptor can serve as the solvent. Use of about 0.7 to 1.5 molar equivalents of the acetylating agent gives a separable mixture of the monoacetyl and diacetyl derivatives wherein the monoacetyl derivative predominates whereas use of about 1.5 to 5 molar equivalents of the acetylating agent gives a separable mixture of the monoacetyl and diacetyl derivatives wherein the diacetyl derivative predominates. A preferred method of acetylation is the reaction of rapamycin with acetic anhydride in an excess of the organic proton acceptor at 0 to 10°C for about one to three hours to obtain a separable mixture of the monoacetyl and diacetyl derivatives of rapamycin.
  • The following example illustrates further this invention:
    • Example 1 Monoacetyl and diacetyl derivatives of rapamycin
  • A solution of 300 mg of rapamycin in 5 ml of dry pyridine was cooled in an ice bath. To this solution, 2.5 ml of acetic anhydride was added and the mixture was stirred at 0 to 5°C for 2 hours. The excess of anhydride was decomposed by careful addition of methanol and the mixture was poured into ice containing 2N hydrochloric acid. The precipitated solids were extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated. The oily residue was chromatographed over silica gel using 20% ethyl acetate in benzene. The appropriate initial fractions were collected, evaporated and crystallised from chloroform-hexane to give rapamycin diacetate (0.165 g): mp 92-93°C; ir (CHCla) 3400, 1730, 1640 and 1620 cm-1; uv max (MeOH) 288 (ε=366), 227 (E=484) and 267 nm (E=363); and nmr (CDCI3) 8 2.05 (s, 3H). The appropriate later fractions were collected, evaporated and crystallised from benzene-hexane to give rapamycin monoacetate (0.058 g): mp 101-102°C; ir (CHCl3) 3400, 1730, 1640 and 1620 cm-1; uv max (MeOH) 288 (E=374), 277 (ε=494) and 267 nm (E=372); and nmr (CDCI,) 8 2.05 (s, 3H) and 2.1 (s, 3H).

Claims (8)

1. A monoacetyl or diacetyl derivative of rapamycin.
2. Rapamycin monoacetate having an mp 101-1020C.
3. Rapamycin diacetate having an mp 92-93°C.
4. An antifungal composition, which comprises a monoacetyl or diacetyl derivative of rapamycin, as claimed in any one of Claims 1 to 3, and a carrier.
5. A pharmaceutical composition comprising a monoacetyl or diacetyl derivative of rapamycin as claimed in any one of Claims 1 to 3 and a pharmaceutically acceptable carrier.
6. A monoacetyl or diacetyl derivative of rapamycin, as defined in any one of Claims 1 to 3 for use as an antifungal, antitumour or anticancer agent.
7. A process for preparing a monoacetyl or diacetyl derivative of rapamycin as defined in Claim 1 which comprises acetylating rapamycin with an acetylating agent containing an acetyl group.
8. A process as claimed in Claim 7 in which the acetylating agent is an acetyl halide selected from acetyl chloride, bromide or iodide or acetic anhydride, and the acetylation is effected in the presence of an organic proton acceptor.
EP81303794A 1980-08-25 1981-08-20 Rapamycin derivatives Expired EP0046661B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT81303794T ATE7920T1 (en) 1980-08-25 1981-08-20 RAPAMYCIN DERIVATIVES.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US181252 1980-08-25
US06/181,252 US4316885A (en) 1980-08-25 1980-08-25 Acyl derivatives of rapamycin

Publications (2)

Publication Number Publication Date
EP0046661A1 EP0046661A1 (en) 1982-03-03
EP0046661B1 true EP0046661B1 (en) 1984-06-13

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US (1) US4316885A (en)
EP (1) EP0046661B1 (en)
JP (1) JPS57118586A (en)
AT (1) ATE7920T1 (en)
CA (1) CA1159054A (en)
DE (1) DE3164177D1 (en)
IE (1) IE51508B1 (en)

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